Muscle Progenitor Cells (MPCs) isolated from skeletal muscle have been shown to be both multipotent and of significant therapeutic value for the repair of various tissues of the musculoskeletal system, including skeletal and cardiac muscles, bone and articular cartilage, yet their ability to undergo neurogenic differentiation has not been fully investigated. We have recently observed that mice and human MPCs are capable of undergoing in vitro and in vivo neurogenic and glial cell differentiation, and inducing functionl healing of sciatic nerve defects in mice. The repair process, determined by histological and immunohistochemical analyses, were also validated by a functional assay (sciatic functional index). Although we have reported that both murine MPCs (mMPCs) and human MPCs (hMPCs) promoted axonal in-growth through their differentiation into glial cells, it is likely that the use of a scaffold to immobilize the injected cells at the injury site could further promote nerve repair. Since we have recently shown that the use of cell sheets as a stem cell delivery vehicle, which immobilizes the cells at the site of injury, further improved the beneficial effect imparted by the stem cells on the injured cardiac and ligamentous tissues, we are proposing to characterize whether the nerve repair process could be enhanced, through the use of a cell sheet comprised of MPCs (Aim #1). Since we have observed that the regenerative potential of MPCs in various tissues correlates with the ability of the cells to induce angiogenesis, we posit that a similar mechanism may explain the beneficial effect imparted by the MPCs in nerve repair. Indeed, it has been observed that VEGF administration can support the growth of regenerating nerve fibers through the process of angiogenesis; moreover, the beneficial effect imparted by bone marrow transplantation on nerve repair appears to occur through the secretion of various trophic factors that promote axon angiogenesis. We are proposing to determine the influence that angiogenesis plays in the nerve healing process (Aim #2) through gain and loss of function experiments using VEGF and sFlt-1 expressing MPCs. Successful completion of these aims will not only provide exciting results for quantitative evidence of the efficacy of MPC transplantation to improve nerve healing, but could also shed light on the mechanism(s) of action by which progenitor cells interact with the microenvironment (especially via angiogenesis) at the site of nerve injury.